Abnormal growth, invasion and metastasis of malignant tumors, such as human lung cancer, breast cancer, colorectal cancer, prostate cancer, liver cancer, pancreatic cancer, lymphoma, melanoma and the like, are important causes of death of tens of thousands of patients every year. The incidence of the malignant tumors is also kept at a certain level, and the malignant tumors have become major diseases that seriously endanger human health. Due to the clinical toxic and side effects of chemotherapy and radiotherapy, the use of these therapies for effective prevention and treatment of the diseases has been limited. Theanine (also known as γ-glutamylethylamide) is a characteristic amino acid indicating the quality of tea. Because theanine has no toxic and side effects as a food component, it is widely used in food industry as a food additive with its amount unlimited. Studies showed that theanine could increase the concentration of an anti-cancer medicament in the tumor and treated human ovarian cancer in a synergistic manner (Sadzuki et al, Toxicol Lett 123: 159-67, 2001). Our previous experiments proved that theanine had the inhibitory effects on liver cancer and lung cancer (Liu, et al, Cytotechnology 59: 211-217, 2009; Zhang et al. Biosci Biotechnol Biochem 2002, 66 (4): 711-6.). In the invention, a novel condensation product of a theanine derivative and a carboxylic acid coumarin derivative, and an intermediate of the condensation product are formed from theanine by chemical method, and the anti-tumor activity of the compounds exceeds that of the anti-cancer medicaments and the theanine.
Histone methyltransferase EZH2 inhibitor and histone deacetylase (HDAC) inhibitor, such as SAHA (suberoylanilide hydroxamic acid), valproic acid, sodium butyrate and the like have been subjected to phase I or phase II clinical tests for blood and solid tumors in the U.S., EZH2 and HDAC are over expressed in a variety of human cancers, including breast cancer, lung cancer, prostate cancer, leukemia, pancreatic cancer, cervical cancer, intestinal cancer, liver cancer and other malignant tumors. A large number of studies on EZH2 and HDAC as targets of anti-cancer medicaments have been carried out in the U.S., and these EZH2 inhibitors and HDAC inhibitors are widely used in the treatment of various tumors and are considered as potential novel anti-cancer medicaments with good application prospects (Yamaguchi et al., Cancer Sci., 10: 355-62, 2010; Denis, et al., Clin Exp Metastasis 25: 183-189, 2008; Kelly et al., Nat Clin Pract Oncol 2: 150-157, 2005; Martinez-Iglesias et al., Clin Transl Oncol. 10: 395-8, 2008).
A nucleoprotein factor NF-κB is considered as a protein factor promoting a variety of tumors, inflammation, cardiovascular diseases, immune deficiency, and other diseases, and is becoming an important target for prevention and treatment of the diseases (Ishii et al., J Clin Biochem Nutr 50: 91-105, 2012).
The high level of receptors such as VEGFR, EGFR, c-Met, and ER-alpha, and abnormal over expression of protein factors such as K-Ras, H-Ras, Akt, Cyclin D1, MMP-9, MMP-2, Dvl-1, Dvl-2, Dvl-3, β-catenin and Bcl-2 which are associated with signal transduction of tumor, are related to occurrence and progression of a variety of tumors, whereas the increase of the level of tumor suppressor proteins p53, p21, E-cadherin, Caspase3, Bax and cytochrome C shows the inhibition of the growth, invasion and (or) metastasis of a variety of cancer cells (Cengel, et al., Neoplasia 9: 341-8, 2007; Huang et al., Biochem Pharmacol 77: 794-803, 2009; Prasad et al, Oncology. 73: 112-7, 2007). Thus, these cancer-related factors become potential important target for prevention and treatment of cancers, and the compounds which can effectively affect the expressive level and activity of these protein factors have broad application prospects in prevention and treatment of the cancers.
The compound as represented by formula (I), which is a condensation product of a theanine derivative and a carboxylic acid coumarin derivative, and an intermediate thereof as represented by formula (II) and formula (III), all of which are provided by the invention, can significantly affect the level and activity of the above mentioned protein factors, and thus have broad prospects in the preparation of inhibitors for prevention and treatment of tumors, inflammation, cardiovascular diseases, immune deficiency diseases and other diseases.